Donepezil, which is chemically known as 2,3-dihydro-5,6-dimethoxy-2[[1-(phenyl methyl)-4-piperidinyl]methyl]-1H-inden-1-one (formula (I)),
is useful in the treatment of patients with various conditions involving memory loss, such as senile dementia of Alzheimer's type (DAT).
U.S. Pat. No. 4,895,481, incorporated herein by reference in its entirety, describes donepezil, its related compounds along with their pharmaceutical acceptable salts including composition and method of treatment using them. The process for the preparation of donepezil is disclosed by the aforesaid product patent involves the conversion of 1-benzyl-4-piperidinone to 1-benzyl-4-piperidine carboxaldehyde in the presence of n-butyl lithium, which on further reaction with 5,6-dimethoxy-1-indanone in the presence of strong base such as lithium diisopropylamide under inert atmosphere followed by reduction of the obtained compound to give the title compound of Formula (I) with an overall yield of 27.4%. U.S. Pat. No. 5,606,064, incorporated herein by reference in its entirety, also discloses the process for the preparation of donepezil, which involves reacting 5,6-dimethoxy indanone and pyridine-4-carboxaldehyde to yield 5,6 dimethoxy-2-pyridin-4-yl methylene-indan-1-one, which upon condensation with benzyl bromide followed by reduction of the obtained compound with platinum oxide to afford the title compound with an overall yield of 58.5%. U.S. Pat. No. 6,252,081 B1, incorporated herein by reference in its entirety, also discloses a process for preparation of donepezil (e.g., examples 1, 2, and 3) that provides a satisfactory yield, but utilizes platinum oxide as a reagent. International Application No. WO 97/22584 discloses a process for preparation of donepezil in the (preparations 1–3 and examples 1–6), with an asserted overall yield of 19.3%.
The prior art procedures for the preparation of donepezil have certain disadvantages, such as the use of hazardous raw materials (e.g., lithium diisopropyl amine and n-butyl lithium), costly raw material (e.g., platinum oxide), low temperatures (e.g., −80° C.), a large number of steps, and/or chromatographic separation of intermediates, as well as relatively low yields. Therefore, there is a continuing need for new methods for preparation of donepezil.